1. Technical Field
The present patent application relates to a stable fixed dose topical formulation comprising an anti-acne agent and an antibiotic, wherein the anti-acne agent is contained in microspheres. Particularly, the present patent application relates to a stable fixed dose topical formulation comprising therapeutically effective amounts of (a) adapalene-containing microspheres and (b) clindamycin, their use for the treatment of acne, and a process for preparing the same.
2. Description of the Related Art
Acne vulgaris is an inflammatory disease of the sebaceous glands characterized by an eruption of the skin, often pustular in nature but not suppurative. Acne vulgaris is a skin condition that affects over 85% of adolescents and young adults. The following are four primary factors that are believed to lead to the formation of acne vulgaris: (1) increased sebum output resulting in oily, greasy skin; (2) increased bacterial activity normally due to an overabundance of propionibacterium acnes; (3) plugging (hypercornification) of the follicle or pilosebaceous duct; and (4) inflammation caused by substances leaking into the dermis. The major physical ramification of acne is the appearance of lesions on the face, chest and/or back areas. Acne lesions change over time from blackheads and whiteheads to inflammatory lesions (papules and pustules) that upon healing may leave pigmentary changes, cysts, or scars. Acne often results in unsightly lesions, particularly on the face, and in some cases may even cause severe scarring.
An effective antiacne therapy should prevent acne recurrence by targeting the early stages of comedogenesis and the precursor of mature acne lesions, the microcomedo. There are a variety of methods for treating acne vulgaris such as, for example, administering various agents either orally or topically to the skin. Nevertheless, acne vulgaris is seldom cured and only can be controlled with difficulty. In no case has a treatment designed for any of the aforementioned causes proven to be uniformly effective. Recently published guidelines recommend topical retinoids with or without benzoyl peroxide for maintenance following initial combination treatment with an antimicrobial. (See, Gollnick H et. al., J Am Acad Dermatol. 2003; 49 (1), S1-S38).
Adapalene, chemically (6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid), is an antiacne agent indicated for the topical treatment of acne vulgaris. It is a white to off-white powder, which is soluble in tetrahydrofuran, very slightly soluble in ethanol, and practically insoluble in water. The molecular formula is C28H28O3 and molecular weight is 412.53. Adapalene is represented by the following structural formula.

Clindamycin, an antibiotic of the lincosamide class, is often used in topical preparations for acne treatment. Clindamycin phosphate is a water soluble ester of the semisynthetic antibiotic produced by a 7(S)-chloro-substitution of the 7(R)-hydroxyl group of the parent antibiotic lincomycin. and has the structural formula represented below:

The chemical name for clindamycin phosphate is methyl 7-chloro-6,7,8-trideoxy-6-(1-methyl-trans-4-propyl-L-2-pyrrolidinecarboxamido)-1-thio-L-threo-D-galactooctopyranoside 2-(dihydrogen phosphate). Although clindamycin phosphate is inactive in vitro, rapid in vivo hydrolysis converts this compound to the antibacterially active clindamycin.
Co-assigned PCT Application Publication No. WO 2006/048747, which describes topical pharmaceutical compositions containing an antiacne compound and antibiotic compound and co-assigned Indian patent application No. 805/MUM/2004 drawn to adapalene microsphere pharmaceutical compositions, are incorporated herein by reference in their entirety.